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J. Biol. Chem., Vol. 278, Issue 48, 47997-48003, November 28, 2003
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Modeling 
-Adrenergic Control of Cardiac Myocyte Contractility in Silico*
¶||
From the
Department of Bioengineering, University of California, San Diego, La Jolla, California 92093-0412, the Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0636, and the ¶Department of Biophysics, Bulgarian Academy of Science, 1113 Sofia, Bulgaria
The 
-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating -adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of 1-adrenergic receptor, and manipulating the affinity of Gs
for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the -adrenergic signaling network may be understood within the context of integrative cellular physiology.
Received for publication, July 30, 2003 , and in revised form, September 10, 2003.
* This work was supported by National Biomedical Computation Resource Grant P41 RR08605 (to A. D. M.), National Space Biomedical Research Institute Project CA00216 (to A. D. M.), National Science Foundation Grant BES-0096482 (to A. D. M.), NHLBI Grant HL-41307 (to L. L. B.) from the National Institutes of Health, National Institutes of Health Grant 5 P50 HL53773-09 (to K. R. Chien), and a Whitaker Foundation Graduate fellowship (to J. J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains Appendices A and B and additional Refs. 1–34.
|| To whom correspondence should be addressed: Dept. of Bioengineering, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0412. Tel.: 858-534-2547; Fax: 858-534-6896; E-mail: amcculloch{at}ucsd.edu.
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